Although oral pre-exposure prophylaxis (PrEP) has been proven effective in reducing HIV infection in high-risk men who have sex with men, heterosexually active women and men, and injecting drug users and approved by the FDA in 2012, uptake has been limited. Significant impediments to PrEP implementation include: system barriers (lack of a medical home and organizational models for implementing PrEP); provider barriers (difficulty identifying those likely to benefit from PrEP, inexperience with PrEP, and concerns about adherence and risk compensation); and user barriers (lack of awareness of PrEP, inability to access providers comfortable with prescribing PrEP, and concerns about stigma and side effects). Cost is not a barrier in New York State, where PrEP is covered by many insurance plans, including Medicaid and is provided to the uninsured. Primary Care for PrEP (PC4PrEP) is a new multilevel structural intervention that will address these diverse barriers to PrEP uptake in underserved communities in the Bronx, NY, a U.S HIV epicenter. It has 4 components: (1) designate a home for PrEP in primary care clinics; (2) train and support primary care providers (PCPs) to prescribe and manage PrEP, and create provider norms that promote the value of PrEP; (3) identify high-risk individuals in primary care clinics using a new PrEP Eligibility Tool; and (4) identify high- risk out-of-care individuals (in collaboration with a community-based organization (CBO) that conducts outreach and HIV testing in HIV-risk groups) and link them to PCPs who can provide PrEP. We will conduct a Phase 2 clinic-randomized futility trial of PC4PrEP in 6 Federally Qualified Health Centers (FQHCs) and 6 non- randomized community HIV testing sites to determine whether PC4PrEP shows promise for increasing the rate of new PrEP prescriptions, assess its effect on outcomes at each stage of our conceptualization of the PrEP Cascade, and assess challenges to PrEP adoption. The Specific Aims are to (1) assess whether PC4PrEP shows promise, measured as the rate of new PrEP prescriptions per clinic per year; (2) through a phased implementation of PC4PrEP components, determine the incremental contribution of each component; (3) evaluate the effects of PC4PrEP on measures of the PrEP Cascade; and (4) assess challenges to PC4PrEP adoption through (a) in-depth interviews with PCPs and support staff about PC4PrEP; (b) in-depth interviews with selected patient-provider dyads to understand their communication about PrEP; and (c) a nested longitudinal qualitative study of patients who initiate PrEP that will include exploration of risk compensation and self-reported adherence augmented by an objective measure of adherence, dried blood spot assays for tenofovir disphosphate. If shown effective, PC4PreP will be highly transferable to other primary care clinic/CBO partnerships in high HIV incidence communities. It is consistent with CDC Guidelines and the Patient Protection and Affordable Care Act in integrating PrEP into primary care practices and is responsive to the 2014 NYS Health Department guidelines, which position PrEP as a first-line intervention for high-risk groups.